title: Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation.
abstract: Multiple myeloma (MM) is the second most common hematologic malignancy. Despite recent treatment advances, it remains incurable. Here, we report that Pim2 kinase expression is highly elevated in MM cells and demonstrate that it is required for MM cell proliferation. Functional interference of Pim2 activity either by short hairpin RNAs or by a potent and selective small-molecule inhibitor leads to significant inhibition of MM cell proliferation. Pim inhibition results in a significant decrease of mammalian target of rapamycin C1 (mTOR-C1) activity, which is critical for cell proliferation. We identify TSC2, a negative regulator of mTOR-C1, as a novel Pim2 substrate and show that Pim2 directly phosphorylates TSC2 on Ser-1798 and relieves the suppression of TSC2 on mTOR-C1. These findings support Pim2 as a promising therapeutic target for MM and define a novel Pim2-TSC2-mTOR-C1 pathway that drives MM proliferation.
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94508, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Tatiana
authors.initials: T
authors.lastname: Zavorotinskaya
authors.forename: Yumin
authors.initials: Y
authors.lastname: Dai
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Niu
authors.forename: Joseph
authors.initials: J
authors.lastname: Castillo
authors.forename: Janet
authors.initials: J
authors.lastname: Sim
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yu
authors.forename: Yingyun
authors.initials: Y
authors.lastname: Wang
authors.forename: John L
authors.initials: JL
authors.lastname: Langowski
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: Pablo D
authors.initials: PD
authors.lastname: Garcia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; C490587:PIM2 protein, human; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases